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Clinical Phenotype Transition in Pemphigus May Suggest Undertreatment with Rituximab: Findings from a Retrospective Single-Centre Analysis of Relapsed Patients
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DOI：10.1159/000550300.png)
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Abstract
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Introduction: Pemphigus is an autoimmune bullous disease caused by autoantibodies against desmoglein (DSG) 1 and/or 3 and comprises two main subtypes: pemphigus vulgaris (PV) and pemphigus foliaceus (PF). PV affects the skin and/or mucosa and includes two forms: mucocutaneous PV (mcPV; anti-DSG1 and anti-DSG3) and mucosal PV (mPV; anti-DSG3). PF, characterized by anti-DSG1 autoantibodies, is limited to the skin. Pemphigus is effectively treated with rituximab, a B-cell-depleting therapy. However, about half of patients relapse, with a subset exhibiting a shift in clinical subtype following relapse, known as clinical phenotype transition. This study aimed to investigate clinical phenotype transition in relapsed pemphigus patients following rituximab treatment. Methods: A single-centre, exploratory retrospective cohort study was conducted, reviewing the medical records of patients with pemphigus who received at least one treatment cycle of rituximab between December 2006 and December 2023. Clinical and immunological data were collected at several time points during the first cycle of rituximab treatment. Results: A total of 109 patients were included, of whom 44% (48/109) achieved sustained complete remission, while 56% (61/109) experienced relapse. Among the 61 patients who relapsed, 26% (16/61) experienced a clinical phenotype transition. All had an initial diagnosis of mcPV. Among these, 75% (12/16) transitioned from mcPV to mPV and 25% (4/16) from mcPV to PF. Clinical phenotype transitioned patients often remained seropositive for anti-DSG3 at clinical remission, a pattern not observed in patients who did not experience a clinical phenotype transition. Conclusions: Clinical phenotype transition was observed exclusively in mcPV patients, suggesting that such changes do not represent a true alteration in disease subtype but rather reflect persistent activity of the same pathogenic autoantibody due to suboptimal B-cell depletion, suggesting undertreatment with rituximab. These findings support the need to refine rituximab treatment regimens to achieve complete B-cell depletion, reduce relapse rates, and optimize long-term disease control in pemphigus. Relapse and disease type changes following rituximab treatment in pemphigus patients: findings from a single-centre review of past cases. Pemphigus is a rare autoimmune blistering disease caused by antibodies attacking proteins (desmoglein [DSG]) that hold skin cells together, causing blisters on the skin and/or mucosa. There are two main types: pemphigus vulgaris (PV) and pemphigus foliaceus (PF). PV can be further divided into mucocutaneous PV (mcPV), affecting both skin and mucous membranes, and mucosal PV (mPV), affecting only the mucous membranes. Rituximab, a treatment that targets certain immune cells called B cells, has greatly improved patient outcomes. However, 11-44% of patients relapse, and in some cases, the clinical pemphigus type (phenotype) changes. In this retrospective study carried out at the Department of Dermatology of the University Medical Center Groningen (UMCG) in the Netherlands, we aimed to understand how often relapse and phenotype change occur, and what immune patterns may be linked to them. We found that 56% of the rituximab-treated pemphigus patients relapsed. In about a quarter of them, the clinical phenotype changed, from mcPV to either mPV or PF. We did not find clear signs that could predict relapse. Changes in clinical phenotype might be associated with higher levels of certain antibodies (anti-DSG3) at remission and elevated plasma cells at relapse. Twelve patients did not improve after the first rituximab treatment, most of whom had received non-standard dosing, suggesting that adequate rituximab dosage is important for treatment success. These results show that relapse and clinical phenotype changes are quite common in rituximab-treated pemphigus patients, and that proper dosing may improve treatment outcomes. This highlights the need to optimize treatment strategies for better disease management.
Keywords:
Pemphigus
Rituximab
Phenotype transition
Autoimmune bullous disease
Immunobullous disease
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